The 10-100 trillion microbes that reside in our gastrointestinal tract form a complex microbial community known as the microbiota. The intestinal microbiota is largely composed of mutualistic bacteria which play many important roles in human health, including aiding in digestion and helping to fend off infection caused by pathogenic bacteria. However, little is known about the strategies employed by resident microbes to resist pathogen invasion or adapt to physiological changes associated with infection such as inflammation and diarrhea. The focus of this project is to understand how members of our resident microbiota resist or adapt to intestinal inflammation caused by the enteric pathogen, Salmonella enterica serovar Typhimurium. Transcriptional profiling of gut-resident mutualists will be used to identify important pathways involved in response to inflammation. Genetic manipulation of the model gut mutualist Bacteroides thetaiotaomicron will be combined with in vivo approaches that utilize gnotobiotic mice colonized with defined simplified microbial communities or colonized with a complete human microbiota to define relevant pathways and the functions of these pathways. These studies will shed light on the mechanisms that underlie the emergence of intestinal pathogens and identify the functional adaptations employed by the microbiota during Salmonella infection in vivo. By understanding this process, new strategies to combat and prevent such infections will become evident. PUBLIC HEALTH RELEVANCE: The goal of this project is to understand how resident intestinal bacteria (the microbiota) functionally adapt to pathogens. Investigating the mechanisms employed by the microbiota to respond to and recover from infection represents a new approach to understand and combat pathogens.